Gastrointestinal sphincters perform two main functions: they keep closed at rest and open at an appropriate time to provide one way transits. The purpose of these studies is to define the genesis of sphincter closure and relaxation (opening). Studies will be performed on the lower esophageal sphincter (composed of smooth muscle fibers) and the upper esophageal sphincter (composed of striated muscle fibers) of the opossum. Our previous studies have shown that basal lower esophageal phincter (LES) closure is not due to tonic neural activity or circulating gastrin. We now plan to investigate the basis of myogenic activity which is responsible for tonic LES closure. Our preliminary studies show that the LES muscle exhibits continous spike activity and slow waves, and that the basal tension is very sensitive to sodium nitroprusside, which known to antagonize the T-system (tonic) of calcium activation of muscle. We will study the extracellular electrical activity, transmembrane potentials in the LES and the effects of modifications of P (phasic) and T-systems of calcium activation of the muscle. Other investigations will extend our studies on the nature of synaptic transmission and of postganglionic inhibitory neuromuscular transmission in LES. These studies will help define the pathogenesis of LES incompetence and achalasia and may help develop their rational therapy. Electromyographic studies with acutely and chronically implanted electrodes and manometric studies will be performed to define the role of cricopharyngeus in upper esophageal sphincter (UES) pressure, genesis of basal pressure and its opening. These studies may help define the pathophysiology of cricopharyngeal achalasia, pahryngeal paralysis and Zenker's diverticulum. The hypothesis developed with studies in the opossum will be tested in patients with these clinical disorders, and rationale of cricopharyngeal myotomy will be defined.